Clin Exp Metastasis (2008) 25:1–3 DOI 10.1007/s10585-008-9161-7

Skeletal complications of malignancy V

Published online: 17 May 2008 Ó Springer Science+Business Media B.V. 2008

The symposium Skeletal Complications of Malignancy V, jointly organized by the Paget Foundation for Paget’s Disease of Bone and Related Disorders and the University of Michigan Medical School took place October 25–27, 2007 in Philadelphia, PA. The audience included more than 300 clinicians and scientists many of whom were young investigators Program topics ranged from cancer stem cells to mechanisms and novel treatments of bone metastasis. The program included plenary sessions and interactive poster sessions. The Program Committee was chaired by: Drs. G. David Roodman, Theresa A. Guise, Kenneth J. Pienta and Allan Lipton. The first session on Cancer Stem Cells and Bone discussed the hypothesis that ‘‘pioneer’’ tumor cells that establish bone metastases from solid tumors are authentic cancer stem cells whose stem cell properties are not cell-autonomous but are determined by their residence in the cancer stem cell niche. The speaker then compared cancer stem cells to hematopoietic stem cells and showed that the two types of cells shared many similar properties. The next presentation discussed stem cell markers such as aldehyde reductase as a characteristic enzyme for several types of stem cells and the utility of a fluorescence-based assay of this enzyme activity to identify living stem cells and progenitor cells. This speaker then discussed ongoing clinical trials at his institution targeting breast cancer stem cells. The next speaker discussed the contribution of bone cells, in particular osteoblasts, to the hematopoietic stem cell niche. She showed that PTH increased the number of osteoblasts and stromal cells, and that these cells were better able to support hematopoietic stem cells in vitro and in vivo. She also reported that the Notch ligand, Jagged1, played an important role in osteoblast support of hematopoietic stem cells, and was increased with PTH treatment. These presentations

highlighted the important research questions that remain such as: (1) is the cancer stem cell niche the same as the hematopoietic stem cell niche? (2) What is the role of osteoblasts in cancer stem cell niches as well as hematopoietic stem cell niches? and (3) what are the mechanisms involved? The second session was on Cancer Cell Dormancy and Bone Metastasis. The first speaker discussed the presence of micrometastasis in the bone marrow as an independent risk factor for relapse and the characteristics of these micrometastases as well as potential mechanisms for controlling cancer stem cell dormancy in the marrow. The next speaker reported on his work on circulating disseminated tumor cells in prostate cancer, and showed that these were very common in patients with no evidence of disease after radical prostatectomy. Another speaker discussed the importance of heparin sulfates and heparin sulfate binding growth factors in tumor biology. The final speaker in this session summarized further studies of disseminated breast cancer stem cells from the bone marrow and showed that bone marrow cells enriched for EpCAM expressed a set of transcripts associated with metastasis and correlated with clinical outcome. Three sessions were on Mechanisms of Bone Metastasis. Several presentations focused on the role of TGF-b, a potent multifunctional cytokine, in promoting the growth of advanced malignancies. Data were presented that suggested that TGF-b was an inhibitor of osteoclast differentiation and a stimulator of osteoblast proliferation in bone metastasis and that TGF-b had an important role in promoting bone metastasis in preclinical models of prostate cancer using PC3 cells. Presentations were also given on the role of integrins and platelets in bone metastasis and on anti platelet therapy as a way to block bone metastasis in models of metastatic melanoma. The possible mechanisms for the stimulatory effects of platelets in bone metastasis

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were also discussed, including the example of platelets secreting lysophosphatidic acid, which is highly mitogenic for many cancer cell types. This phenomenon may explain the contribution of platelets to bone metastasis. Another session on the mechanisms of bone metastasis explored signaling pathways with demonstrated roles in bone metastasis. Presentations discussed the role of Wnts and hypoxia, which are important regulators of these pathways. The importance of the Wnt signaling inhibitor, DKK1, was discussed as well as the role of endothelin-1 in stimulating osteoblastic metastasis. The mechanism responsible for the enhanced effects of hypoxia on promoting bone metastasis was presented and the potential for inhibiting the increased expression of heparin binding growth factors in prostate cancer that occurs with hypoxia was highlighted as a potential therapy for bone metastasis. Two sessions were on Novel Targets for Bone Metastasis. Novel therapies for treating bone metastasis in myeloma and prostate cancer were reviewed. The value of zoledronic acid in preventing skeletal-related events in patients with breast cancer was reviewed and results from clinical trials using the anti-RANK Ligand antibody, denosumab, were presented and compared to trials with zoledronic acid. Another novel target for bone metastasis that was discussed was TGF-b receptor kinase inhibitor, which appears to have added effects in combination with the zoledronic acid in reducing breast cancer cell osteolysis. The final session was on Osteonecrosis of the Jaw (ONJ). The mechanism of action of bisphosphonates was reviewed, and the potential pathophysiology of osteonecrosis of the jaw (ONJ) associated with bisphosphonate

therapy was discussed. One hypothesis for why ONJ occurs predominantly in the jaw that has been proposed is that bone remodeling is increased in the oral cavity, but there are no data to support this hypothesis, nor that bone formation rates differ between the mandible and the humerus. Further, vessel obstruction or decreased vascularity appeared to play no role in the development of ONJ. Histopathologic studies of ONJ have shown that actinomycetes were present in 8 of 8 patient studied, and 5 of these 8 patients had inflammatory infiltrates. Risk factors for developing ONJ were outlined including: time of exposure for patients on bisphosphonate therapy, cumulative risks with prolonged use of bisphosphonates, the question of the type of bisphosphonate playing a role and the possibility that previous dental procedures may be a precipitating factor. The potential role of soft tissue toxicity of bisphosphonates rather than decreased bone remodeling as a cause of ONJ was also discussed. Data were presented regarding the question of whether the doses of bisphosphonate received by patients could be a risk factor. ONJ occurs in a very low percentage of patients (1 per 100,000) receiving an oral bisphosphonate, while patients treated with intravenous bisphosphonates have a much higher incidence. It was concluded that results from both clinical and laboratory studies are still insufficient to demonstrate the mechanism responsible for bisphosphonate-associated ONJ. Thus bisphosphonateassociated ONJ is an important emerging clinical problem, but until a predictive marker for ONJ and an animal model are available as well as predisposing factors are clearly identified, it still remains a very poorly characterized clinical entity in which much additional research is required.

The symposium was supported by unrestricted educational grants from Amgen, Caliper Life Sciences, Celgene Corporation, Faxitron X-ray, LLC, FibroGen, Inc., Immunodiagnostic Systems, Inc., Merck and Company, Millenium Pharmaceuticals and Novartis Oncology. This publication was supported by unrestricted educational grants from Amgen and Novartis Oncology.

In 2007, The Paget Foundation launched a new program, The Bone and Cancer Foundation. The mission of the Bone and Cancer Foundation is to provide information to patients and healthcare providers on the skeletal complications of cancer and to advocate for increased research in the bone metastasis field. Bone and Cancer Foundation publications are available on the website www.boneandcancerfoundation.org or can be obtained in print by calling 212-509-5188 or 1-888-862-0999.

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The Bone and Cancer Foundation 120 Wall Street, Suite # 1602 New York, NY 10005-4035 Tel: 212-509-5188 Toll-free: 888-862-0999 Fax: 212-509-8492 Website: www.boneandcancerfoundation.org Email: [email protected]

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The Paget Foundation 120 Wall Street, Suite # 1602 New York, NY 10005-4035 Tel: 212-509-5335 Toll-free: 800-23-PAGET Fax: 212-509-8492 Website: www.paget.org Website: [email protected]

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